MHC proteins and how they work if you are taking anti-CTLA4 (ipi) or anti-PD-1 (Opdivo or Keytruda) in melanoma

Long ago (2016) I wrote a post about Biomarkers - blood components, circulating tumor cells AND of the tumor itself  which included this:

"Then, there's the examination of the properties of the tumor sample itself.  This article talks about looking at the tumor in regard to how well it is being recognized by the immune system....specifically t-cells:
  

Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.  Johnson, Estrada, Salgado, Sosman, et al.  Nat Commun. 2016 Jan 29.

Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection."

In other words - according to that study, MHC-II positivity in your tumor is good if you want to gain a response from anti-PD-1.

Back in 2014 I wrote: SRS combined with anti-PD1 makes things better in ratties....this one's for you Artie!!!! Where, in an article discussing how combining radiation with immunotherapy can improve responses in melanoma patients, there was this:

"These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 or regulatory T cell (Treg) depletion, resulting in improved local tumor control.  ...radiotherapy increased the percentage of antigen-experienced T-cells and effector memory T-cells.  ...radiotherapy up-regulates tumor associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increased T-cell infiltration into tumors."

This month, there is a new report (with lots of melanoma big dogs as authors) on how MHC proteins affect response to anti-CTLA4 and anti-PD-1.  Here's the link if you want to read it yourself!  http://stm.sciencemag.org

MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma Rodig, Gusenleitner, Jackson,..., Weber, Wolchok, Postoww, Pavlick, Chesney, Hodi.  Science Translational Medicine, July 2018.

MHC-ing immunotherapy response  ~  Currently, there is no way to predict response to anti–CTLA-4 cancer immunotherapy. Using data from two published independent phase 2 clinical trials, Rodig et al. showed that MHC class I expression in advanced melanoma predicted resistance to anti–CTLA-4, but not anti-PD-1, treatment, which may need MHC class II to be effective. These results may explain why patients on combined therapy do better on average, with one drug overcoming the limitations of the other. The combination is also more toxic than single agents; knowing which drug to administer to which patients could make melanoma immunotherapy less taxing without sacrificing efficacy.

Abstract

Combination anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti–programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8+ and CD4+ T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti–CTLA-4, anti–PD-1, or combination therapy. Most (greater than 50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of HLA-A, HLA-B, HLA-C, and B2M, and predicted primary resistance to anti–CTLA-4, but not anti–PD-1, therapy. Melanoma MHC class II membrane expression on greater than1% cells was observed in 55 of 181 cases (30%), was associated with interferon-γ (IFN-γ) and IFN-γ–mediated gene signatures, and predicted response to anti–PD-1, but not anti–CTLA-4, therapy. We conclude that primary response to anti–CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti–PD-1 is associated with preexisting IFN-γ–mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity.

So what is that saying???  Here's an interpretation:  

MELANOMA BIOMARKERS MAY PREDICT RESPONSE TO IMMUNOTHERAPYBy Marilynn Larkin July 26, 2018 Managed Healthcare CONNECT (Reuters Health) - 

Expression of major histocompatibility complex (MHC) class I and class II proteins may help predict a patient's response to melanoma immunotherapy, researchers have found.

In patients with advanced melanoma, treatment with an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) agent plus an anti-programmed cell death protein 1 (PD-1) agent provides a benefit over either therapy alone, but "the shared and unique biological effects derived from inhibiting the two immune checkpoint proteins are still poorly understood," Dr. Scott Rodig of Brigham and Women's Hospital in Boston and colleagues write in Science Translational Medicine, online July 18.

To investigate, the researchers examined the expression of MHC class I and class II proteins in pretreatment biopsy samples from clinical trial patients treated with one of four regimens: ipilimumab (an anti-CTLA-4 agent) followed by nivolumab (an anti-PD-1 agent); nivolumab followed by ipilimumab; ipilimumab alone; or nivolumab and ipilimumab given concurrently.

Partial or complete loss of melanoma MHC class I proteins, seen in 43% of untreated patients, was associated with progressive disease and with primary resistance to single-agent ipilimumab and ipilimumab given before nivolumab, but not to the two agents given concurrently.

By contrast, a deficiency of MHC class I proteins was not associated with nivolumab resistance. According to the authors, that's because PD-1 inhibition is associated with pre-existing interferon-gamma-mediated immune activation, which includes tumor-specific MHC class II proteins and components of innate immunity that come into play when MHC class I is compromised.

Specifically, patients whose tumors had higher pre-treatment levels of interferon-gamma had better outcomes when treated with nivolumab or concurrent therapy, but not with single-agent ipilimumab. Further, MHC class II expression was associated with a higher likelihood of complete or partial responses or stable disease after single-agent nivolumab, rather than progressive disease.

"The real-world implications are that we may be able to identify which patients with melanoma are likely to benefit or not benefit clinically from anti-CTLA-4 or anti-PD-1 therapy based upon an examination of their tumor tissue and their endogenous immune response to the tumor," Dr. Rodig told Reuters Health.

"This is especially important for patients receiving anti-CTLA-4 since the therapy is associated with significant toxicity and if we can spare some patients a therapy that will not be useful and is associated with toxicity, this would be good," he said by email.

"Testing these biomarkers prospectively in a clinical trial will be needed to show whether the tests can be used routinely in the clinic to tailor the choice of immune therapy to individual patients," he added.

"The discovery that Hodgkin lymphoma and melanoma, two very different tumors, have similar means of escaping immune recognition may mean that other common tumors use the same mechanisms," Dr. Rodig said. "We are currently testing this hypothesis in lung cancer and head-and-neck cancers."

Dr. Rohit Sharma, assistant professor of surgery in the division of oncology at UT Southwestern Medical Center in Dallas, said the findings "seem reasonable."

"Systemic therapy for melanoma has been previously limited by few and ineffective options," he said in an email to Reuters Health. "In the past few years there has been a tremendous evolution in the management of melanoma through the discovery of checkpoint and immunotherapy agents. One of the challenges stemming from the rapid influx of (these agents) has been understanding their optimal use in the management of the disease."

The study "begins to identify potential biomarkers that could predict response to specific checkpoint/immunotherapies and also sheds light on potential ways of approaching sequencing of drug therapy," he said. "The potential benefit could be a more enhanced immune response that may translate to improved outcomes for patients."

So across all these studies, the basic results seem consistent.  If your tumors have high expression of MHC class I proteins, you are more likely to need to take CTLA-4 (ipi/Yervoy) in order to gain a response because you are less likely to benefit from anti-PD-1.  On the other hand, if your tumors are high in the expression of MHC class II proteins, you are more likely to be able to gain a good response to anti-PD-1 (nivo/Opdivo or pembro/Keytruda) alone and don't need to risk the side effects from ipi!!

Clear as mud???  While no one thing is an end all/be all in melanoma world, this is ONE MORE simple test that we should start utilizing in order to help melanoma patients find the treatment option that would be best for them!!!  Just say'n!!!  - c

Cure your flu and melanoma too???

Interesting.... 

The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression.  Schrader, Dudek, Schreiber, et al.  Antiviral Res. 2018 Jul 7.

Influenza A virus (IAV) infections are still a major global threat for humans, especially for the risk groups of young children and the elderly. Annual epidemics and sporadically occurring pandemics highlight the necessity of effective antivirals that can limit viral replication. The currently licensed antiviral drugs target viral factors and are prone to provoke viral resistance. In infected host cells IAV induces various cellular signaling cascades. The Raf/MEK/ERK signaling cascade is indispensable for IAV replication because it triggers the nuclear export of newly assembled viral ribonucleoproteins (vRNPs). Inhibition of this cascade limits viral replication. Thus, next to their potential in anti-tumor therapy, inhibitors targeting the Raf/MEK/ERK signaling cascade came into focus as potential antiviral drugs. The first licensed MEK inhibitor Trametinib (GSK-1120212) is used for treatment of malignant melanoma, being highly selective and having a promising side effect profile. Since Trametinib may be qualified for a repurposing approach that would significantly shorten development time for an anti-flu use, we evaluated its antiviral potency and mode of action. In this study, we describe that Trametinib efficiently blocks replication of different IAV subtypes in vitro and in vivo. The broad antiviral activity against various IAV strains was due to its ability to interfere with export of progeny vRNPs from the nucleus. The compound also limited hyper-expression of several cytokines. Thus, we show for the first time that a clinically approved MEK inhibitor acts as a potent anti-influenza agent.

I have ranted to kids and families for years about the importance of avoiding flu through good health care techniques and the flu vaccine!  Looking at data from the CDC from the late 70's through 2007 ~ 3,000 to 49,000 folks died from flu ANNUALLY, depending on the season, just in the United States!!  This study notes that in order for the flu A virus to replicate in our bodies, it requires the RAF/MEK/ERK signaling cascade.

Remember this diagram???  Anyhow, in this report researchers found that in little mice and the petri dish, Trametinib, the first FDA approved MEK inhibitor that we use in melanoma, blocked the replication of some types of flu A!   MEK inhibitors do come with some pretty gnarly side effects, at least for some, so I'm not sure it would be recommended for everyone, but maybe it would be a possibility for high risk folks.  We also have to remember that illness due to flu B makes up a huge part of flu cases as well.  The more important intel from this study may be noting once again how creepily similar cancer and viruses can be!  Thereby, holding out hope that one day, an effective vaccine may be developed for melanoma!!! 

For what it's worth! - c

Sew Chaotically! ~ The Amelia Dress, Green Bee Design

B actually picked up this pattern when we were at Liberty of London in LONDON!!!  He thought the lines would work for me.  Later that week, we found the perfect fabric for it in Walthamstow!  On reading reviews of the make, lots of folks reported that it ran really small.  Since they were so adamant about it, I cut the size large, even though I measured a tad smaller than the medium.  Apart from that I'm not sure I can tell you how I made it!  I don't know that I could replicate it myself!!!  My first level of crazy was spent in the search and study of multiple tutorials on sewing and cutting on the bias.  Next up ~ sitting on the floor for hours cutting all pieces individually and forcing the hind quarters of my brain into action in order to make sure all pieces would match up perfectly!!!  I stitched the darts as indicated. Put the front and back bodice pieces together at the center.  Attached the shoulders.  Used binding rather than the facing for the neckline.  Added the skirt to the front and to the back.  Put in the back zipper.  I stitched the sides together and then ~ did that which I cannot explain.  It involved taking as much as 2 inches off BOTH sides of the bodice and waist and leaving off the pockets because my material was so "flimpy" I didn't think it would stand for it.  I hemmed the "sleeves" by turning under twice.  Though the large was obviously far too large for me, I am glad I cut it, as I could then shape it the way I wanted.  I think it turned out very well!!!

I'm quite proud of my pattern matching!  This dress is really pretty, yet super easy to wear.  And the fabric, whatever it is, washes and dries fabulously!  Sew chaotically! - les

Do glucocorticoids or dexamethasone reduce the effectiveness of immunotherapy in melanoma???

For years and years the vast preponderance of the evidence has demonstrated that folks with significant side effects to immunotherapy not only NEEDED to be treated with steroids in order to deal with the problem presented, but also (thank goodness!!!) showed that steroid treatment, did NOT decrease their survival/response to immunotherapy itself in the end.  Here is one post with links to zillions of reports on studies that looked at this issue:  For Jubes...and the rest of us!!! An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib????

Now, there's this:

High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma.  Faje, Lawrence, Flaherty.Cancer. 2018 Jul 5.

It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy of checkpoint inhibitors. To control for the potential association between immune-related adverse events (irAEs) and improved survival, this study examined a unique cohort of patients who had the same irAE treated with varying glucocorticoid doses.
In total, 98 patients with melanoma who had ipilimumab-induced hypophysitis were identified retrospectively in the Partners Healthcare system using an automated electronic medical record query tool. Patients with melanoma who received ipilimumab at Massachusetts General Hospital without developing hypophysitis were listed in an actively maintained institutional patient database. Glucocorticoid doses for patients with hypophysitis were categorized as low dose (LD) or high dose (HD). Survival analyses were performed for patients who received ipilimumab monotherapy.
Both overall survival (OS) and the time to treatment failure were significantly longer in the LD group compared with the HD group. Median OS and the time to treatment failure were not reached in the LD group and were 23.3 and 14.5 months, respectively, in the HD group. All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months). This advantage was maintained in the HD group versus the nonhypophysitis group. Radiologic and endocrinologic outcomes and symptom resolution did not differ in the LD group versus the HD group.

Among patients with melanoma who had ipilimumab-induced hypophysitis, those who received higher doses of glucocorticoids had reduced survival. This is the first study to demonstrate a potential negative effect of high glucocorticoid doses on the efficacy of checkpoint inhibitors after an irAE. These findings have potential implications for the management of other irAEs.

So, in this study, in order to avoid muddying the waters in regard to survival due to possible differences in outcome caused by the particular side effect itself, the researchers looked at only one side effect - hypophysitis (inflammation of the pituitary gland, which is located at the base of the brain) after melanoma patients were treated with ipilimumab (Yervoy).  In those 98 patients, some folks were treated with high dose glucocorticoids and others were given a low dose.  In those patients, the low dose folks had an overall survival of 23 months vs only 14 months in the high dose group.  But, to me...here is the bigger news ~ "All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months). This advantage was maintained in the HD group versus the nonhypophysitis group."     I do have one question about this study.  Did the folks treated with a higher dose require it in order to deal with their hypophysitis?  Meaning, would a lower steroid dose have been insufficient for an effective response in them?   In the end, despite the fact that these peeps with hypophysitis were treated with steroids....they ALL did better than melanoma peeps with no hypophysitis and no steroids!!!  I think all this reports really tells us is that this pretty horrible side effect seems to come with better survival in melanoma and, of course, we should try to treat side effects using the lowest effective dose of steroids that we can.

Now there is also this (link to entire article and abstract below with thanks to my dear Eric...for sharing it):

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.  Giles, Hutchinson, Sonnemann, et al.  Journal for Immunotherapy of Cancer, June 11, 2018.

Background: Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.

Methods: Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry. 

Results: Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 costimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice. 

Conclusions: Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response. 

First and foremost, this study was done by looking at cells in a petri dish and poor little real live mice.  And, it seems as though the limiting effects created by dexamethasone (a steroid) on T cells was present when the cells were treated with anti-PD-1 but not when treated with ipi (Yervoy).

Well, damn!  When something seems simple in melanoma....we should realize, "NOPE!  Melanoma gonna be crazy!  You'll see!!!"  Still, these are only two studies among YEARS of other research that indicates treatment of side effects caused by immunotherapy, with steroids, did not diminish the good response in patients with melanoma.  And, like the first report above, we have some indication that side effects may even be an indicator of a good response AGAINST melanoma. Additionally, if you are dealing with a potentially deadly side effect...and you die from it because it went untreated....how good is your outcome going to be then????  However, I do think these results tell us that we should continue to look at this issue and be as conservative in management of side effects with steroids (ie doing so only when really needed and with the lowest effective dose) as possible!

Hang in there ratties!  With melanoma it is always a bumpy ride!!! - c

PEG-arginase and complete remission in immunotherapy-resistant melanoma, a case study

While the relatively recently approved treatment options for melanoma (both targeted and immunotherapy) have been absolutely life saving for many, myself included, there are still far too many of us in need of something else!!!  To that end, here is a case study...

To begin, PEG is polyethylene glycol, a vehicle used to make things soluble in water (or the human body) so that a drug/substance can be administered.  It is use in PEG-interferon, for example.  Arginase is an enzyme that breaks down arginine.  Arginine is an essential amino acid needed for protein synthesis.  It is used in the liver, for example, to help excrete ammonia.  Strangely, some melanoma cells are unable to synthesize their own arginine, making them dependent on arginine from other cells.  So now...there is this:

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma.  De Santo, Cheng, Beggs, et al. J Hematol Oncol. 2018 May 18.

Metastatic melanoma is an aggressive skin cancer with a poor prognosis. Current treatment strategies for high-stage melanoma are based around the use of immunotherapy with immune checkpoint inhibitors such as anti-PDL1 or anti-CTLA4 antibodies to stimulate anti-cancer T cell responses, yet a number of patients will relapse and die of disease. Here, we report the first sustained complete remission in a patient with metastatic melanoma who failed two immunotherapy strategies, by targeting tumour arginine metabolism.

CASE PRESENTATION:

A 65-year-old patient with metastatic melanoma who progressed through two immunotherapy strategies with immune checkpoint inhibitor antibodies was enrolled in a phase I study (NCT02285101) and treated with 2 mg/kg intravenously, weekly pegylated recombinant arginase (BCT-100). The patient experienced no toxicities > grade 2 and entered a complete remission which is sustained for over 30 months. RNA-sequencing identified a number of transcriptomic pathway alterations compared to control samples. The tumour had absent expression of the recycling enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC) indicating a state of arginine auxotrophy, which was reconfirmed by immunohistochemistry, and validation in a larger cohort of melanoma tumour samples. 

Targeting arginine metabolism with therapeutic arginase in arginine auxotrophic melanoma can be an effective salvage for the treatment of patients who fail immunotherapy.

For what it's worth! - c

Sew (and live) Chaotically! ~ TURTLES!!! ~ made up in a Hollyburn skirt and a Polly Top to go with!!!

First....there was melanoma.  Then - there was Sally!!!

Here's the back story:  Inauspicious Beginnings

And the pics:  Sally the Loggerhead Turtle

And more pics:  Beach Scenes

Yes, turtles (and dragonflies) are now an intrinsic part of my life and part of the fiber of my family and friends.

Yentle Garden, around Yertle Creek, sports its own turtle (X's 3!!) figurine!  Creek designed by nature, but controlled and turned into a beautiful garden by Roo (aka Yentle!!  HA!).  Here's one of it's early pics:  The tree

More recently, the turtles continue!  As I turned into the drive just the other day, I glanced over to the new garden plot we've added and this is what I saw!  I laughed out loud!  B is one crazy dude, but very good at watering my plants, tolerating my whims, and ever so cute in his bow ties!!! 

See?????!!!!

Then, a few months ago....I got this beautiful surprise!!!

It was from Ruthie!  She does the BEST wrappings!!!!!  

They are always beautiful, perfectly match their contents, and contain the most amazing gifts!!!  Look at this TURTLE fabric!!!!

Sew ~ after pondering my precious turtle fabric for a bit, its destiny became clear.  I decided it would make a perfect Hollyburn skirt (Sewaholic) and needed a little Polly Top  (By Hand London) to go with! The Polly is bound with my own bias binding and the basic quilting cotton (chosen because I liked the color combo) did not like being eased into the curved bodice, wanting to gather instead.  I let it be, leaving some gathers evenly placed at the curves!  I cut the front of the Hollyburn skirt on the fold rather than in two pieces as prescribed by the pattern, so that I could place my turtles just so!!!  Had to shave off and reshape the sides a bit, but I think it worked!!!  Used my self constructed contoured waistband as mentioned in the post above.

The turtle fabric has the perfect attitude and drape for this skirt!!  

With fabric this fab, waste not want not!!!  There is a special baby on the way, where the love and longevity of the turtle plays a beautiful role as well!!!  May this turtle pillow provide cozy comfort for nursing, rocking into sweet dreams, and stories in the days to come!

With much love, my turtle collection continues to grow - all the bounty:  A turtle a day...  
And Ruthie hits a home run again with Miss Flora, nestled front and center!

Roo got a special prize, too!  It was right up her Owl-ly!!!!  Ha!  Are her flowers not beautiful????

With Ms. Turtle living just beneath!

Sometimes life is a beautiful circle that defies anticipation or explanation ~ requiring only our belief in others, love, and...well, turtles!!!   -  love, les

VISTA - an independent negative prognostic factor, but possible avenue for intervention, in melanoma...

As the search continues for ways to predict response and new avenues to attain a response in the treatment of melanoma - there is this:

VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Kuklinkski, Yan, Li, et al. Cancer Immunol Immunother. 2018 May 8.

Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate and the density of PD-1+ inflammatory cells. The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis and multivariate analysis. Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

Get busy researchers!!!  - c

Circulating tumor cells/DNA in melanoma!!! Have I not mentioned this a ZILLION times????

There are many blood (and other fluid) markers, all much easier to collect that actual tumor samples, that can be used to diagnosis melanoma, determine tumor type, prognosis and response to therapy.  Here's a link to zillions of posts:  Neutrophil-to-lymphocyte ratio and outcomes in melanoma. Yep, AGAIN!!!!!  More here:  Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!!

And there is this (with tons of links within) on circulating tumor cells/DNA alone:  ASCO 2017: Circulating DNA to measure response in melanoma

Now, these:

Circulating Tumor Cells in Stage IV Melanoma Patients. Hall, Ross, Bowman, et al.J Am Coll Surg. 2018 May 7.

Management of stage IV melanoma patients remains a challenge. In spite of promising new therapies, many patients develop resistance and progression. The aim of this pilot study was to determine if CTCs are associated with shortened (180-day) progression-free survival (PFS) following a baseline CTC assessment in stage IV melanoma patients.

A baseline CTC assessment was performed in 93 stage IV melanoma patients using a commercially available immunomagnetic system. The presence of greater than/equal to 1 CTC was considered a positive result. A Cox multivariable regression model was used to evaluate the association between presence of CTCs at baseline and PFS, after adjusting for covariables. Kaplan-Meier curves and a log-rank test were used to summarize and compare unadjusted PFS for patients stratified by CTC positivity.

Median follow-up was 17 months; mean age was 55 years. Thirteen of 93 (14%) patients had no evidence of disease (NED) at baseline CTC assessment. One or more CTC was detected in 39/93 (42%) of patients at baseline. CTCs were not associated with primary melanoma features or NED status. Twenty-eight of 93 (30%) patients progressed within 180 days of baseline draw, with 20/39 (51%) of the CTC positive patients relapsing compared to 8/54 (15%) of the CTC negative patients. In adjusted Cox models, a significant association was found suggesting worse PFS within 180 days for CTC positive patients at baseline (vs. CTC negative).

One or more CTCs at baseline were associated with progression within 180 days in stage IV melanoma patients. This information warrants further study of CTCs as a means of identifying patients at high-risk for disease progression.

Measuring circulating tumor cells can predict response and progression!! And, this.....

Quantitative monitoring of circulating tumor DNA predicts response of cutaneous metastatic melanoma to anti-PD1 immunotherapy.  Herbreteau, Vallee, Knol, et al. Oncotarget. 2018 May 18.

Immunotherapies have changed the medical management of metastatic melanoma. However, the early detection of patients who do not respond to these treatments is a key issue. We evaluated the quantitative monitoring of circulating tumor DNA (ctDNA) as an early predictor of response to anti-PD1. Patients treated with anti-PD1 for metastatic mutated melanoma were selected. The somatic alteration detected on the tumor tissue was quantified on plasma DNA by digital PCR (dPCR) at treatment initiation, after 2 and 4 weeks of treatment, and then every 4 weeks until progression. The absence of biological response (defined as a significant decrease in the amount of ctDNA relative to the baseline level) after 2 weeks of treatment was associated with a lack of clinical benefit under anti-PD1. In the presence of a biological response at week 2, detection of subsequent biological progression (significant increase in the amount of ctDNA relative to its nadir) was 100% predictive of progressive disease, on average 75 days prior to radiological detection. Patients with a persistent biological response beyond week 16 did not experience any progressive disease and exhibited sustained responses. In conclusion, we show that quantitative monitoring of ctDNA, using criteria accounting for dPCR measurement imprecision, allows the early and specific detection of patients who do not respond to anti-PD1 therapy.

When circulating tumor DNA was monitored in patients treated with immunotherapy, no significant decrease in the ctDNA measured in the blood was associated with lack of benefit from anti-PD-1 AND an increase in the ctDNA "was 100% predictive of progressive disease, on average 75 days prior to radiological detection."  Think what being able to change treatments, from one that is not working to one that might serve you better, 75 days sooner, could mean for patient outcomes!!!  And, there's this:

Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease. Ballester, Glitza, Douse, et al.  J Neuropathol Exp Neurol. 2018 Jun 4.  

Circulating tumor DNA (ctDNA) refers to tumor-derived cell-free DNA that circulates in body fluids. Fluid samples are easier to collect than tumor tissue, and are amenable to serial collection at multiple time points during the course of a patient's illness. Studies have demonstrated the feasibility of performing mutation profiling from blood samples in cancer patients. However, detection of ctDNA in the blood of patients with brain tumors is suboptimal. Cerebrospinal fluid (CSF) can be obtained via lumbar puncture or intraventricular catheter, and may be a suitable fluid to assess ctDNA in patients with brain tumors. We detected melanoma-associated mutations by droplet-digital PCR (ddPCR) and next-generation sequencing in ctDNA obtained from the CSF (CSF-ctDNA) of melanoma patients with leptomeningeal disease. There is a strong correlation between mutation detection by ddPCR, the presence of circulating tumor cells in CSF and abnormalities in the MRI. However, approximately 30% of CSF samples that were negative or indeterminate for the presence of tumor cells by microscopic examination were positive for CSF-ctDNA by ddPCR. Our results demonstrate that CSF is a suitable fluid for evaluating ctDNA and ddPCR is superior to CSF-cytology for analysis of CSF in melanoma patients with leptomeningeal disease.

Here researchers are simply noting that the cerebral spinal fluid can be monitored in the same manner blood samples can be.

I have been noting these reports for YEARS!!!!!!!!!!!!!!!!!!  If I am aware of these options, then oncologists should know about these study results and assay possibilities far better than I.  These minimally invasive, but highly informative tests, should be readily available and utilized as part of the arsenal to diagnosis, predict response, determine progression, find appropriate therapy, and ultimately save lives of melanoma patients ~ TODAY!!!!  - c

Skin resident memory CD8+ T cells, stimulated by vaccines, protect against melanoma!!!!

I have long hoped vaccines would play a positive role in melanoma treatment!!  Heck, I was a rattie in one of the arms of my nivo trial that included peptide vaccines.  Here is one of my latest posts on the topic:  ASCO 2018!!! We'll start with melanoma vaccines....and a story!

To sum up that post ~ I, along with my fellow ratties, were injected with 6 painful peptide vaccines (as in, they were administered as an injection into our thighs) every 2 weeks for 6 months along with our intravenous infusion of nivolumab.  It turned out that our particular vaccine did us no good.  It is even possible that the injections "sequestered" our helpful CD8+ T cells at the site of the injections.  There is some evidence that rather than revving up our fighting T cells and having them go attack our melanoma, the vaccines simply attracted them, perhaps even fired them up, but then the little suckers just lazed about at the vaccine sites, like camels at an oasis.  (Do camels do that?  I don't really know.)  Anyhow, additional abstracts about vaccine hopes and dreams and scams are included in the post, but... there is also this:

Dendritic cell vaccine induces antigen-specific CD8+ T cells that are metabolically distinct from those of peptide vaccine and is well-combined with PD-1 checkpoint blockade. Nagoaka, Hosoi, Lino, et al.Oncoimmunology. 2017 Nov 2.

The success of immune checkpoint blockade has unequivocally demonstrated that anti-tumor immunity plays a pivotal role in cancer therapy. Because endogenous tumor-specific T-cell responsiveness is essential for the success of checkpoint blockade, combination therapy with cancer vaccination may facilitate tumor rejection. To select the best vaccine strategy to combine with checkpoint blockade, we compared dendritic cell-based vaccines (DC-V) with peptide vaccines for induction of anti-tumor immunity that could overcome tumor-induced immunosuppression. Using B16 melanoma and B16-specific TCR-transgenic T-cells (pmel-1), we found that DC-V efficiently primed and expanded pmel-1 cells with an active effector and central memory phenotype that were not exhausted. Vaccine-primed cells were metabolically distinct from naïve cells. DC-V-primed pmel-1 cells contained the population that shifted metabolic pathways away from glycolysis to mitochondrial oxidative phosphorylation. They displayed better effector function and proliferated more than those induced by peptide vaccination. DC-V inhibited tumor growth in prophylactic and therapeutic settings. Only DC-V but not peptide vaccine showed augmented anti-tumor activity when combined with anti-PD-1 therapy. Thus, DC-V combined with PD-1 checkpoint blockade mediates optimal anti-cancer activity in this model.

Here, in a petri dish, researchers treated melanoma cells with a dendritic vaccine and a peptide vaccine.  They found that only the dendritic vaccine (NOT the peptide vaccine, further corroborating what we real live ratties found in my study) helped increase anti-tumor activity when combined with anti-PD-1 therapy.  Okay.  As far as that goes....

Okay.  I think this is the perfect place to utilize a phrase I created in my childhood, "What's so about that?????"  Well, maybe nothing.  But now, there's this - (and a link to the entire article if you are so inclined):

Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma

Vaccination-induced skin-resident memory CD8⁺ T cells mediate strong protection against cutaneous melanoma. Gálvez-Cancino, López, Menares, et al.  Oncoimmunology. 2018 Mar 19.


Memory CD8⁺ T cell responses have the potential to mediate long-lasting protection against cancers. Resident memory CD8⁺ T (Trm) cells stably reside in non-lymphoid tissues and mediate superior innate and adaptive immunity against pathogens. Emerging evidence indicates that Trm cells develop in human solid cancers and play a key role in controlling tumor growth. However, the specific contribution of Trm cells to anti-tumor immunity is incompletely understood. Moreover, clinically applicable vaccination strategies that efficiently establish Trm cell responses remain largely unexplored and are expected to strongly protect against tumors. Here we demonstrated that a single intradermal administration of gene- or protein-based vaccines efficiently induces specific Trm cell responses against models of tumor-specific and self-antigens, which accumulated in vaccinated and distant non-vaccinated skin. Vaccination-induced Trm cells were largely resistant to in vivo intravascular staining and antibody-dependent depletion. Intradermal, but not intraperitoneal vaccination, generated memory precursors expressing skin-homing molecules in circulation and Trm cells in skin. Interestingly, vaccination-induced Trm cell responses strongly suppressed the growth of B16F10 melanoma, independently of circulating memory CD8⁺ T cells, and were able to infiltrate tumors. This work highlights the therapeutic potential of vaccination-induced Trm cell responses to achieve potent protection against skin malignancies.

You may be thinking, "Interesting, I guess!  But, what's so about that????"

Well, the notation "intradermal" might just be the thing.  It seems from this research that in order to elicit the response Galvez and Lopez are talking about, the vaccine had to mess with the SKIN!!!  Not just be stuck in the body else wise.

Now, give me a minute here.  Remember the mad scientist I live with???  He has been postulating a theory about how triggering a response in dendritic cells and CD8+ T cells that LIVE IN THE SKIN might be the ticket to stimulating the development of vitiligo and thereby a good response AGAINST melanoma for years!

Remember this?  Itching and vitiligo associated with progression free survival after Pembro/Keytruda???!

And this from 2014:  Vitiligo and melanoma  Which includes this commentary:  What I think this says is:  The CD8+ T cells that cause vitiligo, promote response to melanoma.  But, we don't know how. So...the researchers checked a certain type of T cell in mice with no thymus (so the mice couldn't use that part of the process to induce vitiligo) and even so, the active T cells continued to produce vitiligo and protection against melanoma.....and they don't know why!

This from 2015:  Vitiligo....a good prognostic indicator for melanoma!  Which, for the purposes of this discussion is most important for this pic and the commentary beneath it ~

"Vitiligo initiation at site of surgery."  The vitiligo in this poor actual rattie started WHERE THE SKIN WAS CUT!!!!!!!!!!!!!!!!!!!!!

And finally - if you are still with me!!! - there is this from 2011:  Anti-PD-1 is still kicking....

Here, I note:  Apart from that, Brent is developing a rather complicated theory about why which rats, both human and rodent, develop vitiligo, versus those who do not, and thereby have a more positive outcome in regard to their melanoma.  It has to do with the dendritic cells in the skin, their exposure to the melanoma antigen (either from vaccines or from tumor material itself), and the subsequent triggering of the immune response.  I'm telling you...the man is going to win the Nobel Prize for finding the answer to this mess!!  But bottom line, if he's right...does this mean I should be grateful that I am thin, thereby lacking in significant subcutaneous tissue into which the vaccines should have been injected?  Thankful that vaccine material drifted into my dermis either by chance or poor administration techniques by some of the administrators?  Remember Ruthie's dismay when tons of my "Elmer's Glue" came oozing back out of my injection sites? I can't answer those questions, but I'm betting Bentie will figure it out.  I'll just keep reporting.

Okay.  You made it!!!  What all this means, I am not entirely certain.  But, I think research is building more and more of a case about how the skin itself harbors not only evil cutaneous melanoma cells for some of us, but also the key to removing melanoma's protective shroud and killing it!!!  We know that the skin contains:  dendritic cells (of many types!!!), gamma T cells, alpha T cells, CD8+ T cells (specifically the trm [tissue resident memory] cells addressed in this most recent abstract).  We also know that Tissue Resident Memory cells travel up to 2mm per day in the intradermal space.  That's not totally weird or creepy, is it??? TRM's, surveying their territory like a sand shark along the beach, on the look out for tasty minnows or melanoma cells!  Perhaps, the horror of injections that hurt like a booger, then oozed the nasty thick white goo back OUT of the holes poked in my skin, DID make a change in some of my dermal CD8+ Tissue Resident Memory cells.  MAYBE those vaccines did help trigger my vitiligo, as an outward sign of an interior response by my CD8+ T cells against my melanoma.  Maybe the vaccines I was given did not work as initially intended, but did, perhaps, play a role in why I am still here.

Happy 4th.  Here's hoping your dendritic and CD8+ trm cells are busy bees today and every day!!! - c